Illustration of lung cancer transformation and mutations.

Decoding Lung Cancer: How Combined Cell Types Impact Treatment

Avery Sinclair in Health & Wellness December 2025 • 4 min read.

"A New Study Explores the Genetic Landscape of Combined Small Cell and Non-Small Cell Lung Cancers"

Lung cancer remains a leading cause of cancer-related deaths worldwide. It's broadly classified into two main types: non-small cell lung cancer (NSCLC), accounting for approximately 85% of cases, and small cell lung cancer (SCLC), representing about 15%. While these categories help guide treatment, some patients have tumors with a combination of both cell types, known as combined SCLC/NSCLC.

Treating combined SCLC/NSCLC is particularly challenging. Often, NSCLC is treated with targeted therapies that address specific mutations within the cancer cells, while SCLC is more responsive to chemotherapy. However, in combined cases, it's unclear how these different components interact and whether targeted therapies will be effective. Understanding the genetic profiles of these combined cancers is critical for developing better treatment strategies.

A new study published in Lung Cancer delves into the genetic characteristics of combined SCLC/NSCLC tumors. Researchers analyzed tissue samples from patients with both newly diagnosed combined cancers and adenocarcinomas that transformed into SCLC after initial treatment. By comparing the genetic make-up of the different cell types within these tumors, the study provides valuable insights into how these combined cancers develop and respond to treatment.

What Did the Researchers Discover About Combined Lung Cancers?

Illustration of lung cancer transformation and mutations.

The study involved a detailed analysis of tumor samples from eight patients. Four had newly diagnosed combined SCLC/NSCLC, while the other four initially had lung adenocarcinoma that later transformed into SCLC after treatment with tyrosine kinase inhibitors (TKIs). TKIs are drugs that target specific proteins in cancer cells to stop their growth.

Here’s a breakdown of the key findings:

Genetic Consistency: Both the SCLC and NSCLC components within the combined tumors often shared similar mutations, particularly in genes like EGFR, TP53, and RB1.
TP53 and RB1 Inactivation: The inactivation of TP53 and RB1 genes appears to be an early event in the development of combined SCLC/NSCLC. These genes normally suppress tumor growth, so their inactivation promotes cancer development.
ASCL1 Activation: The SCLC component often showed activation of the ASCL1 pathway, which is known to play a role in the development of SCLC.
PI3K/AKT1 Signaling: Activating mutations involving the PI3K/AKT1 signaling pathway were frequently observed in the SCLC component. This pathway is involved in cell growth and survival, and its activation can contribute to cancer development and resistance to therapy.

These findings suggest that combined SCLC/NSCLC may arise from a common origin, with the inactivation of tumor suppressor genes like TP53 and RB1 playing a key role. The activation of the ASCL1 pathway and PI3K/AKT1 signaling may then drive the development of the SCLC component.

What Does This Mean for Patients?

This research provides a deeper understanding of the genetic underpinnings of combined SCLC/NSCLC. This knowledge can help doctors make more informed decisions about treatment, particularly when considering targeted therapies.

The study also sheds light on why some combined SCLC/NSCLC tumors may not respond well to TKIs, even if they have EGFR mutations. The presence of other mutations, particularly those involving the PI3K/AKT1 pathway, may contribute to resistance.

While more research is needed, these findings suggest that a comprehensive genetic analysis of both the SCLC and NSCLC components is crucial for tailoring treatment to individual patients. This may involve repeat biopsies or larger surgical specimens to ensure accurate assessment of the tumor's genetic make-up. As research continues, new therapies that target the specific pathways involved in combined SCLC/NSCLC may offer improved outcomes for patients with this challenging disease.

About this Article -

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This article is based on research published under:

DOI-LINK: 10.1016/j.lungcan.2018.10.006, Alternate LINK

Title: Clinicopathological And Genomic Comparisons Between Different Histologic Components In Combined Small Cell Lung Cancer And Non-Small Cell Lung Cancer

Subject: Cancer Research

Journal: Lung Cancer

Publisher: Elsevier BV

Authors: Mong-Wei Lin, Kang-Yi Su, Te-Jen Su, Chia-Ching Chang, Jing-Wei Lin, Yi-Hsuan Lee, Sung-Liang Yu, Jin-Shing Chen, Min-Shu Hsieh

Published: 2018-11-01

Everything You Need To Know

Why is treating combined Small Cell Lung Cancer/Non-Small Cell Lung Cancer so difficult?

Combined Small Cell Lung Cancer/Non-Small Cell Lung Cancer (SCLC/NSCLC) presents a treatment challenge because NSCLC is typically addressed with targeted therapies aimed at specific mutations, while SCLC is more responsive to chemotherapy. The difficulty lies in understanding how these different components interact and whether targeted therapies will be effective in a combined case, making it crucial to understand their genetic profiles for better treatment strategies.

What main genetic similarities and differences did the researchers discover between the Small Cell Lung Cancer and Non-Small Cell Lung Cancer components in combined tumors?

The study found that both the Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC) components within combined tumors often shared similar mutations, notably in genes like *EGFR*, *TP53*, and *RB1*. Additionally, the inactivation of *TP53* and *RB1* appears to be an early event in the development of combined SCLC/NSCLC. The SCLC component often showed activation of the *ASCL1* pathway and activating mutations involving the PI3K/AKT1 signaling pathway.

Why is the inactivation of the TP53 and RB1 genes so critical in the development of combined Small Cell Lung Cancer/Non-Small Cell Lung Cancer?

The inactivation of *TP53* and *RB1* genes appears to be critical because these genes normally act as tumor suppressors. When they are inactivated, they lose their ability to control cell growth, promoting the development and progression of cancer. In the context of combined Small Cell Lung Cancer/Non-Small Cell Lung Cancer (SCLC/NSCLC), their inactivation is considered an early event.

What is the significance of the activation of the ASCL1 pathway and PI3K/AKT1 signaling in Small Cell Lung Cancer?

The activation of the *ASCL1* pathway and PI3K/AKT1 signaling is significant because the *ASCL1* pathway is known to play a crucial role in the development of Small Cell Lung Cancer (SCLC). Activating mutations involving the PI3K/AKT1 signaling pathway are frequently observed in the SCLC component, and this pathway is involved in cell growth and survival, contributing to cancer development and potential resistance to therapy. The study showed that these activations may drive the development of the SCLC component.

What are tyrosine kinase inhibitors (TKIs), and what does it mean if lung adenocarcinoma transforms into Small Cell Lung Cancer after TKI treatment?

Tyrosine kinase inhibitors (TKIs) are drugs that target specific proteins in cancer cells to stop their growth. In the context of the study, some patients initially had lung adenocarcinoma that later transformed into Small Cell Lung Cancer (SCLC) after treatment with TKIs. This suggests that while TKIs can be effective initially, cancer cells may evolve and develop resistance, leading to the emergence of SCLC. The implication is that continuous monitoring and adaptation of treatment strategies are crucial in patients receiving TKIs.